Prolonged oral corticosteroid treatment in patients with systemic lupus erythematosus: An evaluation of 12-month economic and clinical burden

BACKGROUND: Prolonged, high-dose corticosteroid treatment for systemic lupus erythematosus (SLE) is associated with substantial health care costs, health care resource utilization (HCRU), and adverse events (AEs). OBJECTIVE: To compare all-cause health care costs, HCRU, and oral corticosteroid (OCS)–related AEs among patients with prevalent OCS use and patients without OCS use. METHODS: This retrospective, longitudinal cohort study (GSK study 214100) used claims data from the IQVIA Real-World Data Adjudicated Claims – US, IQVIA, Inc, database between January 1, 2006, and July 31, 2019, to identify patients with SLE. Patients with at least 1 OCS pharmacy claim during the study period and continuous OCS use during the 6-month pre-index (baseline) period (index date is the date of the first OCS claim following 6 months’ continuous use) formed the “prevalent OCS use cohort.” This cohort was subdivided based on the level of OCS exposure during the 12-month observation period, ie, the number of 6-month periods of greater than 5 mg/day OCS use (0, 1, or 2). Patients without OCS claims formed the “no OCS use cohort.” All patients had continuous enrollment during the baseline and observation periods, had at least 1 inpatient or at least 2 outpatient SLE diagnosis codes during baseline, and were aged at least 5 years at index. A 2-part model, a generalized linear regression model with a negative binomial distribution, and a multivariate logistic regression model were used to compare health care costs, HCRU, and the odds of developing an OCS-related AE between cohorts, respectively. RESULTS: The no OCS use and prevalent OCS use cohorts included 21,517 and 16,209 patients, respectively. Adjusted health care cost differences (95% CI) were significantly lower for the no OCS use cohort vs all prevalent OCS use exposure categories ($5,439 [$4,537-$6,371] vs $17,856 [$16,368-$19,498]), driven by inpatient stays and outpatient visits; HCRU was also significantly lower (adjusted incidence rate ratios vs no OCS use cohort [95% CI]: 1.20 [1.16-1.23] vs 1.47 [1.41-1.52]). Health care costs and HCRU increased with increasing length of OCS exposure. OCS-related AEs occurred more frequently for all prevalent OCS use exposure categories vs the no OCS use cohort (odds ratio [95% CI]: 1.39 [1.25-1.55] vs 2.32 [2.02-2.68]), driven by hematologic/oncologic and immune system–related AEs. The mean (SD) average daily dose of OCS increased with increasing periods of prevalent OCS use (2.5 [1.3], 6.9 [31.1], and 34.6 [1,717.3] mg/day, respectively, for patients with 0, 1, and 2 periods of OCS use). CONCLUSIONS: Prevalent OCS use incurs a substantial clinical and economic burden, highlighting the need for restricted OCS doses and durations.


METHODS:
This retrospective, longitudinal cohort study (GSK study 214100) used claims data from the IQVIA Real-World Data Adjudicated Claims -US, IQVIA, Inc, database between January 1, 2006, and July 31, 2019, to identify patients with SLE. Patients with at least 1 OCS pharmacy claim during the study period and continuous OCS use during the 6-month pre-index (baseline) period (index date is the date of the first OCS claim following 6 months' continuous use) formed the "prevalent OCS use cohort." This cohort was subdivided based on the level of OCS exposure during the 12-month observation period, ie, the number of 6-month periods of greater than 5 mg/day OCS use (0, 1, or 2). Patients without OCS claims formed the "no OCS use cohort." All patients had continuous enrollment during the baseline and observation periods, had at least 1 inpatient or at least 2 outpatient SLE diagnosis codes during baseline, and were aged at least 5 years at index. A 2-part model, a generalized linear regression model with a negative binomial distribution, and a multivariate logistic regression model were used to compare health care costs, HCRU, and the odds of developing an OCS-related AE between cohorts, respectively.

Plain language summary
Steroids are often used in the treatment of lupus. In this study, patients with lupus who were treated with oral steroid medications had greater health care costs, greater use of health care resources, and more adverse events than patients not treated with steroids. This difference in clinical and economic burden is mostly due to an increased use of hospital facilities. These results support careful consideration of the risks and benefits of steroid treatments in lupus.

Implications for managed care pharmacy
The results of this study highlight the increased health care costs, health care resource utilization, and occurrence of oral corticosteroid (OCS)-related adverse events among patients with at least 6 months of OCS use. This burden increases with increasing duration of OCS use greater than 5 mg/day. An awareness of the risks of steroid treatment is essential to determine the most appropriate OCS dose and duration and ultimately improve the management of lupus and reduce the health care burden.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder characterized by fluctuating periods of elevated disease activity (SLE flares) and reduced disease activity (remission). 1 Manifestations of SLE vary widely, but they commonly affect the musculoskeletal, dermatologic, renal, neuropsychiatric, pulmonary, hematologic, and cardiovascular organ systems. 2,3 Current treatment options in SLE include managing disease symptoms, reducing the frequency and severity of flares, and reducing the risk of organ damage. 4,5 Corticosteroids are the cornerstone of SLE treatment because of their rapid and potent anti-inflammatory and immunosuppressive properties. 6,7 In the United States, approximately 70% of patients with SLE will receive corticosteroids, 8 with high doses frequently prescribed in response to flares. 9 However, prolonged use of corticosteroids is associated with several adverse events (AEs). Although some of these AEs are potentially reversible (eg, type 2 diabetes mellitus and hypertension), others, including bone fractures caused by osteoporosis, avascular necrosis, and cataracts, represent irreversible damage. 7,10 As a result, much of the organ damage observed in SLE can be attributed to corticosteroids, particularly following long-term use. 11 The extent of corticosteroid-related organ damage is also dependent on the dose; data from the Hopkins Lupus Cohort demonstrated that each 1-mg increase in the average prednisone daily dose was associated with a 3% increase in the risk of developing new organ damage. 12,13 Therefore, recommendations for SLE management aim to use the lowest possible prednisone-equivalent corticosteroid dose (<7.5 mg/day) and withdraw when possible. 4 Additionally, corticosteroid use in SLE incurs a substantial economic burden, [14][15][16][17] with health care costs and health care resource utilization (HCRU) increasing with increasing doses. 15,16 The burden of long-term and short-term corticosteroid use in oral corticosteroid (OCS)-naive patients has previously been identified. 16,18 However, an up-to-date and extensive analysis of the clinical and economic burden of prevalent (≥6 month) corticosteroid use in patients with SLE is lacking.
This study assessed the economic and clinical burden associated with prevalent OCS use in patients with SLE by evaluating health care costs among patients with at least 6 months of prednisone-equivalent OCS use greater than 5 mg/day compared with patients with no OCS use. Secondary objectives were to compare HCRU and the occurrence of OCS-related AEs in these cohorts and to describe treatment patterns.

STUDY DESIGN
This retrospective, longitudinal, observational study (GSK study 214100) utilized medical and pharmacy claims data from the IQVIA Real-World Data Adjudicated Claims -US, IQVIA, Inc, database from January 1, 2006, to July 31, 2019, to identify patients with SLE ( Figure 1).
Patients with SLE were categorized into 1 of 2 cohorts: the prevalent OCS use cohort and the no OCS use cohort. The index date of the prevalent OCS use cohort was defined as the date of the first OCS pharmacy claim following 6 months of continuous OCS use (no gaps in days supply >30 days); the index date of the no OCS use cohort was imputed based on the distribution of time between the start of the continuous eligibility period and the index date for the prevalent OCS use cohort. The baseline period was defined as the 6 months prior to the index date, and the observation period was defined as the 12 months following the index date.

ETHICAL APPROVAL AND INFORMED CONSENT
The IQVIA Real-World Data Adjudicated Claims -US, IQVIA, Inc, database is de-identified in compliance with the patient confidentiality requirement of the Health Insurance Portability and Accountability Act; therefore, no institutional review board or informed consent was required for this study.

STUDY POPULATION
Eligible patients were required to be aged at least 5 years at index with a diagnosis of SLE (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 710.0x or ICD-10-CM codes M32.0, M32.1x, M32.8, and M32.9; ≥2 outpatient medical claims or ≥1 inpatient/emergency department claim) during the baseline period and have continuous enrollment in a health plan for at least 6 months prior to index and at least 12 months following index. cumulative damage and/or SLE medication utilization to determine severity. The flare algorithm was developed using definitions from the Lupus Foundation of America 21 and criteria based on the British Isles Lupus Assessment Group index. 24 Pharmacy claims were used to calculate the prednisoneequivalent OCS dose (see the Supplementary Material for the list of OCS medications) during the observation period, for which the average daily dose (ADD; observation period) was based on the total number of days in the observation period and was calculated as follows: All-cause and specific categories of HCRU were reported for the baseline and observation periods, including inpatient stays, emergency department visits, outpatient visits, and Patients in the prevalent OCS use cohort were required to have at least 1 OCS pharmacy claim during the study period and continuous OCS use during the baseline period. The prevalent OCS use cohort was further categorized into 3 exposure categories based on the number of 6-month periods (0, 1, or 2) of average daily prednisone-equivalent OCS use greater than 5 mg/day during the observation period. Patients included in the no OCS use cohort were required to have no pharmacy claims for OCS at any time during the study period.

VARIABLES AND OUTCOMES
Patient demographic characteristics (sex, age at index, geographic region, health insurance type, and year of index), clinical characteristics (diagnosing physician specialty, Quan-Charlson comorbidity score, comorbidities [identified using ICD-9-CM and ICD-10-CM codes, Supplementary Table 1, available in online article], and concomitant medications commonly prescribed for SLE), and all-cause health care costs were captured during the baseline period.
SLE disease severity and the frequency/severity of flare episodes were assessed for each patient during the baseline period and the observation period and were classified in mutually exclusive categories as mild, moderate, or severe (definitions are provided in the footnotes of Table 1). Categories were determined using previously published health care utilization-based algorithms 19-23 derived from the severity of diagnoses listed on administrative claims data using the ICD-9-CM diagnosis, Healthcare Common Procedure Coding System, and Current Procedural Terminology procedure codes. The disease severity algorithm combined elements of disease activity with

FIGURE 1
Study Design OCS treatment patterns were reported during each exposure category of the observation period. Treatment patterns included the cumulative OCS dose, ADD, and number of OCS claims per patient per 6 months.

STATISTICAL ANALYSIS
Patient demographic and clinical characteristics were summarized using means and SDs for continuous variables and relative frequencies and proportions for categorical variables. Comparisons between the prevalent OCS use cohort and the no OCS use cohort during the baseline period used other encounters (including ambulance, assisted living facilities, comprehensive rehabilitation facilities, custodial care facilities, hospice/home care services, intermediate care facilities, psychiatric facilities, and skilled nursing facilities).
Incidence of OCS-related AEs (cardiovascular, metabolic and endocrine, central nervous system, bone and muscle, infections, ophthalmologic, gastrointestinal, dermatologic, and hematologic/oncologic) were reported during the observation period. Corticosteroid-related AEs were included based on package inserts for commonly prescribed corticosteroids or systematic literature searches. 14    Adjusted odds ratios (ORs) were estimated using a multivariate logistic regression model to compare the odds of developing an OCS-related AE between the prevalent OCS use cohort and the no OCS use cohort. ADD analyses were stratified by age group (5-17 years and ≥18 years) and Wilcoxon rank sum tests used for statistical comparisons between age groups.

BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS
Of the 399,000 patients with at least 1 SLE claim identified, 16,209 were included in the prevalent OCS use cohort and 21,517 in the no OCS use cohort (Supplementary Figure 1).
During the observation period, 33.3%, 27.7%, and 39.0% of patients in the prevalent OCS cohort had 0, 1, and 2 6-month periods of OCS use greater than 5 mg/day, respectively. antimalarials, immunosuppressants, and biologics), disease severity, flares, and OCS ADD. This approach included fitting a logistic regression model for the probability of observing a positive cost and fitting a generalized linear regression model, with a γ distribution and log link, among patients who incurred health care costs during the observation period. Nonparametric bootstrap procedures with 999 replications were applied to determine 95% CIs and P values. Sensitivity analyses for the association between OCS use and all-cause health care costs were carried out using alternative definitions for OCS use: ADD (days supply) instead of ADD (observation period) and a 7.5 mg/day instead of 5 mg/day OCS dose threshold.
HCRU comparisons between the exposure categories of the prevalent OCS use cohort and the no OCS use cohort used adjusted incidence rate ratios (IRRs), estimated using a generalized linear regression model with a negative binomial distribution to account for overdispersion.  Fewer patients in the no OCS use cohort were classified as having moderate or severe SLE during the baseline period vs patients with 0, 1, and 2 periods of prevalent OCS use greater than 5 mg/day (20.0% vs 68.0%, 82.7%, and 92.5% respectively; all P < 0.01). Fewer patients in the no OCS use cohort also experienced at least 1 flare during the baseline period vs the prevalent OCS use cohort with 0, 1, and 2 periods of OCS use greater than 5 mg/day (46.6% vs 70.9%, 74.2%, and 75.5% respectively; all P < 0.01) and across all flare severities (mild: 11.8% vs 20.2%, 20.9%, and 22.3%; moderate: 38.8% vs 60.8%, 64.6%, and 63.6%; and severe: 1.7% vs 4.2%, 7.0%, and 9.7%; all P < 0.01; Table 1).
Baseline all-cause health care costs in the no OCS use cohort were lower than for patients with 0, 1, and 2 periods of prevalent OCS use greater than 5 mg/day ($7,520 vs $13,668, $18,992, and $22,761, respectively; all P < 0.01), driven by total medical costs in both cohorts (Table 1).

HCRU.
Over the observation period, most patients in both cohorts had at least 1 health care visit (prevalent OCS use cohort: ≥99.6%; no OCS use cohort: 93.0%; Table 2). After adjusting for baseline covariates, incidence rates per patient per year were significantly higher for each of the prevalent OCS use exposure categories vs the no OCS use cohort for all-cause, outpatient, inpatient stays, and emergency all P < 0.01). Fewer patients in the no OCS use cohort experienced at least 1 flare in the observation period (60.8%) vs patients with 0, 1, and 2 periods of prevalent OCS use >5 mg/day (89.2%, 94.1%, and 94.9% respectively; all P < 0.01) and had a lower flare severity (Supplementary Table 2

Discussion
Findings from this large population-based cohort revealed that, compared with patients with no OCS use, patients with prevalent (≥6 months) OCS use had significantly higher health care costs, HCRU, and odds of experiencing OCSrelated AEs in the following 12 months of observation. These differences increased with increasing periods of prevalent OCS use, with the greatest costs, HCRU, and odds of experiencing OCS-related AEs observed for patients with 2 periods of OCS use greater than 5 mg/day. Outpatient and inpatient costs accounted for approximately 40%-46% and 19%-28% of costs in patients with prevalent and no OCS use, respectively. These findings remained robust following adjustment for baseline covariates, including disease severity, concomitant medication, and flares, as well as in the sensitivity analyses using alternative definitions for OCS use.
The substantial medical costs and HCRU incurred by patients with OCS use has previously been characterized. [15][16][17] Two claims-based analyses in the United States demonstrated an association between increasing corticosteroid dose with increasing HCRU and health care costs; 15,16 low doses of corticosteroid (≤5 or ≤7.5 mg/day) incurred 1.4 times the costs of patients with no OCS use, whereas higher doses (>15 mg/day and >20 mg/day) incurred 2.8 times and 3.6 times the costs of patients with no OCS use. Similar to the present study, inpatient, emergency department, and outpatient visits were greater in patients with corticosteroid use than those without corticosteroid use, with costs largely driven by hospitalizations. 15,16 Two recent studies conducted using the IQVIA Real-World Data Adjucated Claims -US, IQVIA, Inc, database showed that patients with established OCS use (≥12 months of continuous OCS use) or newly initiated OCS use experience a significantly greater clinical and economic burden than patients with no OCS use; adjusted cost differences (95% CI) following 2 periods of OCS use greater than 5

OCS TREATMENT PATTERNS
Cumulative OCS Dose. The cumulative dose of OCS per 6-month period increased with the number of periods of prevalent OCS use greater than 5 mg/day. Patients with 0, 1, and 2 periods of prevalent OCS use had cumulative mean (SD) doses of 464.9 (241.7), 1,257.6 (5,689.9), and 6,323.5 (314,259.4) mg/6-month period, respectively. for patients with 2 periods of prevalent OCS use greater than 5 mg/day. This may indicate patients receiving more frequent bursts of high-dose OCS rather than consistently high doses of OCS.
Strengths of this study include the identification of a large cohort of patients with SLE who had prevalent or no OCS use during a 13-year period. Associations between prevalent OCS use and health care costs and HCRU were strong and remained robust even after adjusting for baseline characteristics and using different definitions for OCS daily dose.

LIMITATIONS
Several limitations should be considered. First, the study utilized medical and pharmacy claims sourced from the IQVIA Real-World Data Adjudicated Claims -US, IQVIA, Inc, database, which was primarily developed for health service and payment purposes; therefore, confounders such as ethnicity, clinical biomarkers, and measures of disease activity (eg, the Systemic Lupus Erythematosus Disease Activity Index) were unavailable. This study attempted to control for confounding by indication bias to a feasible extent by adjusting for disease severity and frequency/severity of flares during the baseline period. Results indicate that increased OCS utilization, rather than OCS use due to more severe disease, is associated with increased HCRU, health care costs, and risk of OCS-related AEs. However, the possibility of residual confounding bias should be considered given the use of claims data, which are not intended for research purposes. Second, the cost and HCRU data were limited to medical services captured within the claims database and could not account for records or patient practices (eg, over the counter medications) not captured in the database. As such, patients with dual coverage or supplemental health insurance may not have their costs and HCRU accurately captured, and there may be missing data or misclassification in the calculation of drug dose and duration. Third, the study population was limited to patients with prevalent OCS use with prespecified continuous eligibility; therefore, the results may not be generalizable to patients without consistent health care access or patients who received care outside of a managed care population (eg, Medicare or Medicaid). Finally, as the study was observational, interpretation of a causal relationship between OCS use and the risk of OCS-related AEs, as well as determining whether the AEs were truly corticosteroid emergent, was not possible.
OCS treatment is substantial and increases with increasing length of exposure. The use of effective and safe treatments that allow for a reduction of OCS dose and duration may lower rates of HCRU and AEs and improve the overall management of disease and reduce health care burden.

DISCLOSURES
This study (GSK Study 214100) was funded by GSK. GSK was involved in designing the study, contributing to the collection, analysis, and interpretation of the data, supporting the authors in the development of the manuscript, and funding the medical writing assistance. All authors, including those employed by GSK, approved the content of the submitted manuscript and were involved in the decision to submit the manuscript for publication.
Dr DerSarkissian, Dr Duh, and Mr Benson are employees of Analysis Group, which received research funding from GSK to conduct this study. Dr Wang, Ms Gu, and Mr Vu are former employees of Analysis Group. Mr Bell is an employee of GSK and holds stocks and shares in the company. Ms Averell and Dr Huang are former employees of GSK and held stocks and shares in the company at the time of the study.